-
Journal of Pediatric Gastroenterology... Jul 2024Linaclotide, a guanylate cyclase-C agonist, was recently approved in the United States for the treatment of children 6-17 years of age with functional constipation (FC)....
OBJECTIVES
Linaclotide, a guanylate cyclase-C agonist, was recently approved in the United States for the treatment of children 6-17 years of age with functional constipation (FC). This study evaluated the dose-response, safety, and efficacy of 4 weeks of linaclotide compared with placebo in children 2-5 years of age with FC.
METHODS
In this phase 2, randomized, double-blind, placebo-controlled, multidose study, 35 children with FC (based on Rome III criteria) were randomized 3:1 to receive linaclotide (18, 36, or 72 μg, for groups 1, 2, and 3, respectively) and 5:1 to receive linaclotide 9, 18, 36, or 72 μg (group 4), or matching placebo. Key endpoints were the changes from baseline in overall spontaneous bowel movement (SBM) frequency (SBMs/week), stool consistency, and straining, as well as the proportion of days with fecal incontinence during the study intervention period. Adverse events (AEs) were recorded.
RESULTS
Of the randomized patients, 34 (97.1%) completed the treatment period and 33 (94.3%) completed the posttreatment period. Mean change from baseline over the treatment period for three of the four key efficacy endpoints showed greater improvement in the linaclotide 72 μg group versus placebo. A dose-response trend was seen for stool consistency in patients receiving linaclotide. Four patients randomized to linaclotide experienced treatment-emergent AEs, one of which was treatment-related (mild diarrhea). All AEs were mild or moderate and none were severe.
CONCLUSIONS
Linaclotide was well tolerated in this pediatric population and an efficacy trend was seen with linaclotide 72 μg versus placebo.
PubMed: 38962910
DOI: 10.1002/jpn3.12306 -
Journal of Personality Jul 2024Does experiencing adversity engender kindness, and if so, for whom? Two studies tested the hypothesis that adversity predicts increased pro-social outcomes, and that...
BACKGROUND
Does experiencing adversity engender kindness, and if so, for whom? Two studies tested the hypothesis that adversity predicts increased pro-social outcomes, and that this relationship is strongest for individuals who view others as good and trustworthy, or benevolent.
METHOD
In Study 1, a cross-sectional survey design was utilized, and in Study 2 a longitudinal survey was conducted.
RESULTS
In Study 1 (N = 359), the number of lifetime adverse life events was associated with increased volunteering, empathic concern, and self-reported altruism. The association of adversity and altruism was stronger for those with greater benevolence beliefs. In Study 2 (N = 1157), benevolence beliefs were assessed, and in subsequent years, adverse life events were reported. The number of past-year adverse life events predicted more volunteering and charitable involvement, but only among people with high benevolence beliefs.
CONCLUSION
Exposure to adversity may be associated with increased pro-social behavior among those with higher benevolence beliefs. In part, this could be due to benevolence beliefs increasing the expectation that one's efforts will be appreciated and reciprocated.
PubMed: 38962876
DOI: 10.1111/jopy.12960 -
Clinical Pharmacology and Therapeutics Jul 2024Bispecific T-cell Engagers (TCEs) are promising anti-cancer treatments that bind to both the CD3 receptors on T cells and an antigen on the surface of tumor cells,... (Review)
Review
Bispecific T-cell Engagers (TCEs) are promising anti-cancer treatments that bind to both the CD3 receptors on T cells and an antigen on the surface of tumor cells, creating an immune synapse, leading to killing of malignant tumor cells. These novel therapies have unique development challenges, with specific safety risks of cytokine release syndrome. These on-target adverse events fortunately can be mitigated and deconvoluted from efficacy via innovative dosing strategies, making clinical pharmacology key in the development of these therapies. This review assesses dose selection and the role of quantitative clinical pharmacology in the development of the first eight approved TCEs. Model informed drug development (MIDD) strategies can be used at every stage to guide TCE development. Mechanistic modeling approaches allow for (1) efficacious yet safe first-in-human dose selection as compared with in vitro minimum anticipated biological effect level (MABEL) approach; (2) rapid escalation and reducing number of patients with subtherapeutic doses through model-based adaptive design; (3) virtual testing of different step-up dosing regimens that may not be feasible to be evaluated in the clinic; and (4) selection and justification of the optimal clinical step-up and full treatment doses. As the knowledge base around TCEs continues to grow, the relevance and utilization of MIDD strategies for supporting the development and dose optimization of these molecules are expected to advance, optimizing the benefit-risk profile for cancer patients.
PubMed: 38962850
DOI: 10.1002/cpt.3361 -
Expert Opinion on Drug Safety Jul 2024Limited knowledge exists regarding the hemorrhagic risk resulting from potential interactions between P-glycoprotein (P-gp) inhibitors and direct oral anticoagulants...
BACKGROUND
Limited knowledge exists regarding the hemorrhagic risk resulting from potential interactions between P-glycoprotein (P-gp) inhibitors and direct oral anticoagulants (DOACs). Utilizing the Food and Drug Administration Adverse Event Reporting System (FAERS) data, we analyzed hemorrhagic adverse events (AEs) linked with the co-administration of P-gp inhibitors and DOACs, aiming to offer guidance for their safe and rational use.
METHODS
Hemorrhagic events associated with P-gp inhibitors in combination with DOACs were scrutinized from the FAERS database. Hemorrhagic signals mining analysis was performed by estimating the reported odds ratios (RORs) and further confirming the findings using additive and multiplicative models and a combination risk ratio (PRR) model.
RESULTS
Our analysis covered 4,417,195 cases, revealing 11,967 bleeding events associated with P-gp inhibitors. We observed a significantly higher risk of bleeding with the combination of apixaban and felodipine (ROR 118.84, 95% CI 78.12-180.79, additive model 0.545, multiplicative model 1.253, PRR 22.896(2450.141)). Moreover, consistent associations were found in the co-administration analyses of rivaroxaban with dronedarone and diltiazem, and apixaban with losartan, telmisartan, and simvastatin.
CONCLUSION
Our analysis of FAERS data analysis unveils varying degrees of bleeding risk associated with the co-administration of P-gp inhibitors and DOACs, underscoring the importance of vigilance about them in clinical practice.
PubMed: 38962834
DOI: 10.1080/14740338.2024.2376693 -
Clinical Pharmacology and Therapeutics Jul 2024Studies using real-world data (RWD) can complement evidence from clinical trials and fill evidence gaps during different stages of a medicine's lifecycle. This review... (Review)
Review
Studies using real-world data (RWD) can complement evidence from clinical trials and fill evidence gaps during different stages of a medicine's lifecycle. This review presents the experience resulting from the European Medicines Agency (EMA) pilot to generate RWE to support evaluations by EU regulators and down-stream decision makers from September 2021 to February 2023. A total of 61 research topics were identified for RWE generation during this period, covering a wide range of research questions, primarily generating evidence on medicines safety (22, 36%), followed by questions on the design and feasibility of clinical trials (11, 18%), drug utilization (10, 16%), clinical management (10, 16%), and disease epidemiology. A significant number of questions were related to the pediatric population and/or rare diseases. A total of 27 regulatory-led RWD studies have been conducted. Most studies were descriptive and aimed at estimating incidence and prevalence rates of clinical outcomes including adverse events or to evaluate medicines utilization. The review highlights key learnings to guide further efforts to enable the use and establish the value of real-world evidence (RWE) for regulatory decisions. For instance, there is a need to access additional fit-for-purpose and representative data, and to explore further means to provide timely evidence that meets regulatory timelines. The need for early interactions and close collaboration with study requesters, e.g., from the Agency's scientific Committees, to better understand the research question is equally important. Finally, the review provides our perspective on the way forward to maximize the potential of regulatory-led RWE generation.
PubMed: 38962830
DOI: 10.1002/cpt.3355 -
Archives of Physiotherapy 2024Worldwide many countries provide direct access in physiotherapy. The aim of this scoping review was to synthesize the available evidence on the quality of primary care... (Review)
Review
INTRODUCTION
Worldwide many countries provide direct access in physiotherapy. The aim of this scoping review was to synthesize the available evidence on the quality of primary care musculoskeletal physiotherapy from different perspectives.
METHODS
Systematic searches were conducted in three databases up to September 2022. Studies were included when regarding assessment of at least one of the following perspectives: patient (quality of Life, patient satisfaction, pain, functioning, adverse events), provider (treatment compliance, responsibility, liability, status, prestige, job satisfaction), and society (number of referrals, amount of medical imaging, medication use, number of sessions needed for rehabilitation, and overall costs and cost-effectiveness). Selection and methodological quality assessment of systematic reviews were performed. Data extraction and analysis were performed separately for systematic reviews and individual primary studies.
RESULTS
Five systematic reviews as well as 17 primary studies were included. From a patient perspective, no significant effect of direct access was found for pain and a tendency in favour of direct access was found for quality of life, functioning, and well-being. Concerning providers, higher treatment compliance was found in direct access to physiotherapy and decision-making was more accurate. From a societal perspective, significant differences in favour of direct access physiotherapy were found for waiting time, prescribed medication, and medical imaging. In addition, there was a tendency towards lower health care costs.
CONCLUSIONS
Emerging evidence suggests that direct access physiotherapy could provide at least equal quality of care for patients and better opportunities for providers and the society on selected outcomes.
PubMed: 38962745
DOI: 10.33393/aop.2024.3023 -
Frontiers in Medicine 2024There is limited insight into the current disease burden and everyday clinical management of moderate-to- severe AD in Poland, Czechia, Russia, and Turkiye. Therefore,...
Disease burden, clinical management and unmet treatment need of patients with moderate to severe atopic dermatitis; consensus statements, insights and practices from CERTADE (Central/Eastern EU, Russia, Turkiye AD Experts) Delphi panel.
BACKGROUND
There is limited insight into the current disease burden and everyday clinical management of moderate-to- severe AD in Poland, Czechia, Russia, and Turkiye. Therefore, this study aimed to get information-driven insights regarding the current disease burden and clinical management of patients with moderate-to-severe AD with common and differentiating aspects of the patient journey and establish a consensus.
METHODS
In this modified 2-round Delphi panel, 133 questions were asked in total to 27 dermatologists. A consensus was achieved when 70% of the panel members strongly agreed or agreed (or strongly disagreed or disagreed) with an item. Statements with <40% agreement dropped from the Delphi rounds and were not repeated.
RESULTS
The results state that AD has a significant impact on the quality of life for both patients and their families with social and economic consequences in these countries. While there were significant dissimilarities regarding the current treatment approach by preference order and treatment duration among participants, there was also a high percentage of consensus on literature and guideline-based statements. Current topical therapies and the immune response modifiers were not found to be sufficient by panelists to cover the therapeutic needs of patients with moderate-to-severe AD. Moreover, panelists highlighted the significant burden of adverse events with the off-label use of currently available immunosuppressants.
CONCLUSIONS
These results underlined that there is a significant disease burden with an unmet treatment need for patients with moderate-to-severe AD in Poland, Czechia, Russia, and Turkiye.
PubMed: 38962737
DOI: 10.3389/fmed.2024.1402493 -
International Journal of Breast Cancer 2024In Peru, breast cancer (BC) stands as the most predominant malignancy neoplasm among women. Trastuzumab has marked a significant milestone in the management of this...
In Peru, breast cancer (BC) stands as the most predominant malignancy neoplasm among women. Trastuzumab has marked a significant milestone in the management of this disease. It has been shown to improve prognosis in human epidermal growth factor receptor 2 (HER2)-expressing female patients, but its repercussions and efficacy are yet to be analyzed in a context with limited resources. The study population is made of woman patients aged 18 years and older diagnosed with HER2-positive BC at Instituto Nacional de Enfermedades Neoplásicas (INEN, Lima, Peru) during 2019-2021 and treated with at least one dose of subcutaneous trastuzumab. We reviewed medical records to register treatment characteristics, adverse events (AEs), disease progression, and survival status. We considered a median follow-up time of 36 and 45 months for progression and survival status. The majority of patients were over 50 years old (54.29%). Tumor size averaged 19.7 ± 16.1 mm. Lymph nodes were present in 44.78% of patients. Most patients received adjuvant chemotherapy (63.8%) as first-line treatment. Descriptive analyses of treatment outcomes revealed a 30% toxicity rate, primarily attributed to arthralgia (47.62%), followed by diarrhea, fatigue, and injection site reactions, with relatively lower discontinuation rates compared to larger scale studies. Differences in demographic, clinical, and treatment characteristics were not statistically significant concerning the emergence of AEs ( > 0.05). Progression appeared in nine patients, and the overall survival (OS) rate stood at 98.6% and 92.8%, respectively, during a median follow-up of 36 and 45 months. The research suggests that subcutaneous trastuzumab is comparable in effectiveness and safety to the intravenous administration. Regional-specific studies may provide valuable insights into demographic factors influencing treatment outcomes in Peru or other countries. Furthermore, it could represent a more accessible alternative, potentially enhancing patient adherence and optimizing healthcare resource logistics.
PubMed: 38962673
DOI: 10.1155/2024/9551710 -
Digital Journal of Ophthalmology : DJO 2024We present the case of a 65-year-old man with bilateral keratoconus and history of bilateral penetrating keratoplasty (PK) who developed gradual visual decline in the...
We present the case of a 65-year-old man with bilateral keratoconus and history of bilateral penetrating keratoplasty (PK) who developed gradual visual decline in the left eye due to cataract formation. Following successful left eye cataract surgery and monofocal, non-toric intraocular lens (IOL) in-the-bag implantation, the patient experienced persistently low uncorrected distance visual acuity (UDVA) due to high residual refractive error and intolerance to contact lenses. A supplementary toric IOL was placed in the ciliary sulcus, but subsequent rotational instability of the lens required repeated realignment. Despite two attempts at IOL repositioning, the rotational instability persisted, necessitating the replacement of the original Sulcoflex IOL with a toric, implantable Collamer lens. Following the implantation of the toric ICL, the patient achieved excellent UDVA with no adverse events over a 4-year follow-up period. This case highlights the potential rotational instability associated with toric piggyback IOLs in keratoconic, post-PK, pseudophakic eyes and the special considerations on choosing the type of piggyback lens in these eyes.
Topics: Humans; Male; Aged; Pseudophakia; Lenses, Intraocular; Visual Acuity; Keratoplasty, Penetrating; Prosthesis Design; Lens Implantation, Intraocular; Keratoconus; Refraction, Ocular; Postoperative Complications; Reoperation; Rotation
PubMed: 38962666
DOI: 10.5693/djo.02.2024.02.002 -
Cureus Jun 2024Cardiac amyloidosis (CA) involves the abnormal deposition and accumulation of amyloid proteins in the heart muscle. A hallmark of disease progression is declining heart... (Review)
Review
Cardiac amyloidosis (CA) involves the abnormal deposition and accumulation of amyloid proteins in the heart muscle. A hallmark of disease progression is declining heart function, which can lead to structural irregularities, arrhythmias, and ultimately heart failure. Atrial fibrillation (AF) is the most common arrhythmia that presents in CA patients, and this arrhythmia is significant because it can moderately increase the risk of patients developing intracardiac thrombi, thereby putting them at risk for thromboembolic events. The management of this complication entails the use of anticoagulants like vitamin K antagonists and direct oral anticoagulants to reduce the risk of thrombus formation. This article seeks to review AF in CA and the use of anticoagulation therapy for the management and reduction of thromboembolic risk. The major conclusions of this review are centered around the need for safe administration of anticoagulant therapy to CA patients, regardless of their CHA2DS2-VASc risk score. This review highlights the importance of taking a multidisciplinary or collaborative approach to CA treatment to ensure that all aspects of this multifaceted disease can be properly managed while minimizing adverse events like bleeding risk and drug-drug interactions.
PubMed: 38962633
DOI: 10.7759/cureus.61557